The peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor that belongs to nuclear receptor superfamily such as steroid receptor, retinoid receptor and thyroid receptor. Moreover, there exist three isoforms (α type, γ type and δ (or β) type) in this receptor, which are identified in various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). Thereamong, the PPARα is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids (Endocrinology, 1995, 137, 354), positively or negatively controlling the expressions of genes relevant to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipo protein (AI, AII, CIII) genes relevant to the metabolisms of cholesterol and triglyceride. The PPARβ is expressed ubiquitously in the tissues of organisms, including nerve cells. The PPARγ is highly expressed in the adipocytes and involved in the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). At present, the physiological significance of PPARδ is unclear. In this way, each isoform of PPAR is fulfilling specific functions in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPARα exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577). This strongly suggests the relevance between activation of PPARα and decreasing effect of lipids (cholesterol and triglyceride) in blood.
On the other hand, as the therapeutic drugs for hyperlipidemia used mainly at present, fibrates and statins are known. However, the fibrates have only weak decreasing effect of cholesterol, while the statins have weak decreasing effect of free fatty acids and triglycerides. Moreover, with respect to the fibrates, adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported, hence the development of a therapeutic drug for hyperlipidemia due to specific mechanism that exhibits no such adverse effects is desired.
When considering the present situation of such conventional therapeutic drugs for hyperlipidemia, and the role on the regulatory function of lipometabolism and the connection to the pathology of hyperlipidemia of transcription factor called PPARα, which has become clear until now, if a compound that binds directly to PPARα, in particular, to human PPARα as a ligand and is capable of potently activating human PPARα could be created, it would be expected to become a therapeutic drug that exhibits the decreasing effect of lipids (both of cholesterol and triglyceride) in blood due to specific mechanism.
As endogeneous ligands of PPARα, eicosanoids in hydroxyeicosatetraenoic acid (HETE) group produced via oxidation with cytochrome P-450, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB4 being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
On the other hand, as compounds with similar structure to the inventive compounds, for which the agonistic activity on PPARα is reported, compounds represented by a general formula (A)
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or which may have substituents, phenoxy group which is unsubstituted or which may have substituents, or benzyloxy group which is unsubstituted or which may have substituents, R2 denotes a lower alkyl group with carbon atoms of 1 to 4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, and, when R2 is a lower alkyl group with carbon atoms of 1 to 4 or 2,2,2-trifluoroethyl group, R3 denotes a hydrogen atom or lower alkyl group with carbon atoms of 1 to 4 and, when R2 is a lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, R3 denotes a hydrogen atom, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], in Jpn. Kokai Tokkyo Koho JP 2001/55367, compounds represented by a general formula (B)
[wherein R1 denotes a lower alkyl group, lower alkoxy group, trifluoromethyl group, trifluoromethoxy group or benzyloxy group which may have substituents, R2 denotes a hydrogen atom, lower alkyl group or lower alkoxy group, R3 denotes a lower alkoxy group, and A denotes —CH2CONH—, —NHCOCH2—, —CH2CH2CO—, —CH2CH2CH2—, —CH2CH2O—, —CONHCH2—, —CH2NHCH2—, —COCH2O—, —OCH2CO—, —COCH2NH— or —NHCH2CO—], in WO01/92201, and compounds represented by a general formula (C)
[wherein R1 denotes a hydrogen atom, hydroxyl group, alkyl group or the like, L denotes a single bond, double bond, alkylene group or the like, M denotes a single bond, alkylene group or the like, T denotes a single bond, alkylene group or the like, W denotes a carboxyl group, group represented by —CON(R11)R12 or the like,  denotes a single bond or double bond, X denotes an oxygen atom, alkenylene group or the like, Y denotes an aromatic hydrocarbon group which may have hetero atom, or the like, and ring Z denotes a hydrocarbon group which may have hetero atom], in WO01/251281 are known. However, in the specifications of these patent applications, (2S)-2-ethylphenylpropanoic acid having a group represented by a formula
[wherein R1 denotes a halogen atom or trifluoromethyl group, R2 denotes a hydrogen atom, halogen atom or trifluoromethyl group, and, when R2 denotes a hydrogen atom, R3 denotes a halogen atom or trifluoromethyl group and, when R2 denotes a halogen atom or trifluoromethyl group, R3 denotes a hydrogen atom, halogen atom or trifluoromethyl group], being a feature of the inventive compounds, is not disclosed.
The subject of the invention is to provide compounds that have a different structure from that of publicly known compounds aforementioned, that have potent agonistic activity on PPARα and exhibit potent effect in vivo, and further that have excellent properties in the points of safety, persistence, etc.